Early antidepressant medications, e.g., tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), are effective because they enhance either noradrenergic or serotonergic mechanisms or both. Unfortunately, these compounds block cholinergic, histaminergic and alpha-1-adrenergic receptor sites, interact with a number of other medications and bring about numerous undesirable side effects. Several chemically unrelated agents have been developed and introduced in the past decade to supplement the early antidepressants. These include selective inhibitors of the reuptake of serotonin (the selective serotonin reuptake inhibitors (SSRIs)) or noradrenaline (reboxetine) or both (SNRIs: milnacipran and venlafaxine), as well as drugs with distinct neurochemical profiles, such as mirtazapine, nefazodone, moclobemide and tianeptine.
Milnacipran (racemic cis-2-(aminomethyl)-N,N-diethyl-1-phenyl-cyclopropanecarboxamide) is a well-characterized small molecule that functions through several mechanisms, including re-uptake inhibition of serotonin and noradrenaline. This agent was discovered and originally developed for treatment of major depressive disorders (“MDD”). See, e.g., U.S. Pat. No. 4,478,836. Clinical development was initiated in the late 1980s, and a large number of toxicology, pharmacology, mechanism and safety trials were conducted at that time. Through the mid-1990s numerous human clinical trials were conducted, leading to approvals for MDD in France and over 20 other countries beginning in 1997.
The safety and efficacy of milnacipran for treatment of MDD have been extensively documented throughout this process. In addition, milnacipran has been evaluated on a more limited basis for the treatment of anxiety and chronic pain. Milnacipran has an excellent safety profile, backed by an extensive database consisting of over 400,000 patient-exposures during more than 4 years of commercial marketing. Safety has been characterized in male and female adults, ranging in age from 18 to over 80, and in patients with various concomitant illnesses. Moreover, relatively few contraindications have been discovered.
Milnacipran inhibits with essentially equal potency the reuptake of serotonin and noradrenaline, with no detectable affinity for any neurotransmitter receptor studied. See generally Puech, A. et al. Int. Clin. Psychopharmacol. 1997, 12, 99-108. A review of the studies comparing milnacipran, placebo and active comparator antidepressants provides clear-cut evidence of its efficacy in both severe and moderate depression in hospitalized and community settings. Meta-analyses of the original data of controlled trials involving 1032 patients, comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs), show that milnacipran provides antidepressant efficacy similar to that of imipramine and significantly superior to that of the SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of the tricyclic antidepressants (TCAs) with fewer cholinergic side-effects. The tolerability of milnacipran was comparable to that of the SSRIs, with a higher incidence of dysuria with milnacipran, and a higher frequency of nausea and anxiety with the SSRIs. Therefore, milnacipran is a therapeutic option in depression, offering a clinical efficacy in the range of the TCAs combined with a tolerability equivalent to that of the SSRIs.
Antidepressants of all types represent a common form of therapy for a variety of chronic pain conditions, and studies have demonstrated that the analgesic effects of these drugs are independent of their influence on mood. Agents that interfere with the reuptake of norepinephrine, particularly tricyclic antidepressants (TCAs), have demonstrated superior analgesic efficacy compared to agents that selectively block the reuptake of serotonin. Unfortunately, many patients are unable to tolerate the side effects associated with TCAs. Thus, there has been an effort to find agents that affect norepinephrine reuptake, but improve upon the side effect profile of TCAs.
Milnacipran and duloxetine have been compared in an experimental nerve injury model known as spinal nerve ligation (SNL). SNL induces behavioral signs in rats that are similar to human states of neuropathic pain, including increased sensitivity to light touch (mechanical hypersensitivity) and increased sensitivity to heat (thermal hypersensitivity). The results of the study indicated that milnacipran and duloxetine both reversed SNL-induced thermal hypersensitivity, but that milnacipran was more effective in reversing the SNL induced thermal hypersensitivity than duloxetine. This finding was consistent with other studies indicating that drugs that interfere with norepinephrine reuptake, compared to drugs that interfere more with serotonin reuptake, have superior analgesic properties. Neither milnacipran nor duloxetine reversed mechanical hypersensitivity, consistent with the profile of amitriptyline, a TCA, in this model.
Despite its acceptance as a highly desirable drug for the treatment of depression and other disorders, including fibromyalgia, there are side effects associated with the use of milnacipran. There are also occasional issues with patient compliance. Although milnacipran is effective in treating major depressive episodes, more suitable methods are needed. These methods include, e.g., administering more efficacious amounts of milnacipran, i.e., above 100 mg daily dosages of milnacipran. These daily dosages would preferably result in an improved efficacy of the milnacipran, the maintenance of excellent patient tolerability, the maintenance of a positive patient safety profile (e.g., dose limiting toxicity), a suitable peak plasma concentration (Cmax) of milnacipran, and/or a once-a-day (QD), as opposed to twice-a-day (BID).
Adverse reactions to the oral administration of milnacipran include at least one of the following: nausea, vomiting, headache, tremulousness, anxiety, panic attack, palpitations, urinary retention, orthostatic hypotension, diaphoresis, chest pain, rash, weight increase, back pain, constipation, vertigo, increased sweating, agitation, hot flushes, tremors, fatigue, somnolence, dyspepsia, dysoria, nervousness, dry mouth, abdominal pain, irritability, and insomnia. One frequently mentioned dose-limiting side effect of Milnacipran was gastrointestinal disturbances, including nausea and vomiting with increasing frequency after doses of 100 mg or above. The highest incidence of nausea and vomiting was observed in a pharmacokinetic study in which subjects fasted prior to study drug administration. Clinical trials in which study drug was administered at meal time showed significantly improved gastrointestinal tolerability. These data indicate that local Milnacipran effects (direct influence on the stomach surface) are quite substantial. No information is available regarding local effects of pure enantiomers of milnacipran. In addition, a direct irritant effect of milnacipran on gastric mucosa was found in preclinical studies. The incidence of certain adverse events increases with dosage, including nausea, vomiting, sweating, hot flushes, palpitations, tremor, anxiety, dysuria, and sleep disturbances.
The (+)-dextro enantiomer of milnacipran (F2695, (+)-1S,2R-milnacipran) is roughly twice as active in inhibiting norepinephrine and serotonin reuptake as the racemic mixture. See Viazzo et al. Tetrahedron Lett. 1996, 37, 4519-4522; Deprez et al. Eur. J. Drug Metab. Pharmacokinet. 1998, 23, 166-171. Moreover, the (−)-levro enantiomer of milnacipran (F2696, (−)-1R,2S-milnacipran) is much less potent. See id.